This study aimed to investigate the spectrum of deafness gene variants among newborns in Hainan Province, China. We also evaluated the effectiveness of a combined hearing and genetic screening approach in this region. Special attention was given to differences between the Han and Li populations, as well as the relationship between genetic variants and hearing follow-up outcomes. From October 2020 to June 2022, 2128 newborns in Hainan (1502 Han, 626 Li) received combined hearing and genetic screening. Hearing screening followed national standards. Genetic screening was carried out using targeted next-generation sequencing of GJB2, SLC26A4, GJB3, and MT-RNR1. Infants with detected variants or those referred from hearing screening received diagnostic audiological follow-up. Among the 2128 newborns (1502 Han, 626 Li), 514 (24.15%) carried deafness gene variants. Variants in GJB2 were the most common, with a carrier rate of 22.51% (479/2128). The GJB2 c.109G > A (p.V37I) variant was the hotspot variant, with an overall carrier rate of 20.91% (445/2128). This rate was significantly higher in the Li ethnic group (28.6%, 179/626) than in the Han group (17.7%, 266/1502; P < 0.01). Thirty-seven newborns carried biallelic pathogenic variants in GJB2. Nine newborns (0.42%) were diagnosed with hearing loss at three months, and all 9 had biallelic GJB2 variants (7 homozygous c.109G > A, 1 compound heterozygote c.109G > A/299_300del, and 1 homozygous c.235del). Longitudinal follow-up of children with biallelic c.109G > A variants showed delayed-onset and progressive hearing loss, with confirmed cases increasing at ages 2 and 4. There are no significant differences in mean ABR thresholds or their standard deviations between Han and Li individuals with homozygous GJB2 c.109G > A mutations at 4 years of age. For patients with biallelic c.109G > A variants, the current setting of ABR thresholds may lead to missed diagnosis. This study showed a high prevalence of deafness gene variants, especially GJB2 c.109G > A, among newborns in Hainan, with clear ethnic differences. Combined screening was effective in identifying genetic hearing loss, including delayed-onset and progressive cases that could be missed by hearing screening alone. These findings support adding genetic screening to regional newborn screening programs and highlight the need for long-term monitoring of at-risk children.

Osteogenesis imperfecta (OI) is a rare genetic bone disorder for which treatment options remain limited. Disease-specific induced pluripotent stem cells (iPSCs) offer a valuable model to investigate its underlying pathological mechanisms. Peripheral blood cells from two OI patients were reprogrammed into iPSCs. Transcriptomic sequencing and proteomic analysis were employed to systematically identify differentially expressed genes (DEGs) and proteins (DEPs) between OI-iPSCs and normal iPSCs. Bioinformatics approaches were subsequently applied for enrichment analysis and protein-protein interaction network investigation. OI-iPSCs were successfully established. Integrated multi-omics analysis identified 671 common DEGs and 636 common DEPs. These molecules were significantly enriched in metabolic pathways, with the oxidative phosphorylation pathway being particularly prominent. Further cross-omics screening revealed 22 genes that were differentially expressed at both the mRNA and protein levels. Among these, the focal adhesion protein VCL emerged as a central hub within the protein-protein interaction network. Through multi-omics analysis, this study revealed widespread dysregulation of metabolic pathways in OI-iPSCs, suggesting that targeted interventions on specific metabolic pathways may represent a novel therapeutic strategy for OI. VCL emerged as a key candidate molecule, warranting further functional validation in subsequent studies. These findings provide new insights into the mechanisms of OI and potential avenues for therapeutic development.

Escherichia coli (E. coli) is a leading cause of bloodstream infections (BSIs) globally, with multidrug-resistant (MDR) strains complicating treatment outcomes. In South Africa, genomic data on such isolates remain scarce. To elucidate the genomic landscape of E. coli isolates from bloodstream infections (BSIs) collected over a one-year period in the uMgungundlovu District, South Africa, with a focus on the resistance and virulence genes, mobile genetic elements (MGEs), genetic synteny, sequence types (STs), and phylogenomic context. Twenty-five non-duplicate E. coli isolates were recovered from blood cultures and subjected to antimicrobial susceptibility testing. All twelve MDR isolates underwent whole-genome sequencing and bioinformatic analysis. The MDR isolates comprised six distinct STs, notably high-risk international lineages ST131 (33.3%) and ST69 (25.0%), spanning five phylogroups, predominantly B2 and D. Eight O: H serotypes were identified, with O25:H4 and O45:H16 being most frequent. CH-typing revealed dominant CH types CH40-30 (ST131) and CH35-27 (ST69) and fimH alleles such as fimH30 and fimH27. The isolates encoded β-lactamases, including blaCTX-M-15, blaTEM-1B and blaOXA-1, frequently co-located with MGEs. Notably, blaCTX-M-15 was chromosomally integrated within a Tn3–ISEcp1 transposon unit, while blaTEM-1B and blaOXA-1 were associated with diverse plasmid-associated syntenic architectures flanked by IS1, IS91, or integron-associated regions. Other antibiotic resistance genes were detected, conferring resistance to aminoglycosides (aph(3’)-Ia, aac(3)-IIa, aac(3)-IIe, aadA1, aadA2), sulfonamides (sul1, sul2) and trimethoprim (dfrA variants). A diverse array of virulence genes was identified, associated with adhesion, iron acquisition, serum resistance, and toxin production. Phylogenomic clustering revealed close relationships between local ST131/ST69 isolates and counterparts across Africa. The study identifies diverse MDR E. coli clones circulating in bloodstream infections, notably high-risk lineages ST131, ST69 and ST10, with complex resistance and virulence gene arsenals facilitated by MGEs. These insights reinforce the imperative for genomic surveillance to guide infection control and antibiotic stewardship in high-burden settings.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as NAFLD (non-alcoholic fatty liver disease), is a growing global concern, affecting nearly a third of the world’s population. This umbrella term covers a range of liver pathologies, from reversible disease stages like simple steatosis, to irreversible conditions such as cirrhosis and hepatocellular carcinoma (HCC). MASLD, which may result from metabolic risk factors like obesity and type 2 diabetes, is projected to increase due to a rise in sedentary lifestyles. This review addresses genetic influences that predispose to disease development, including the role of risk-conferring and protective/preventive alleles. The epistatic relationships between genetic variants can significantly influence the development and progression of MASLD. Key genetic variants, such as those located in the PNPLA3, TM6SF2, and MBOAT7 genes, often interact to exacerbate MASLD severity and play key roles in lipid metabolism and liver inflammation. For example, the co-expression of certain PNPLA3 and TM6SF2 variants increases the risk of advanced fibrosis and HCC. Some variants located in HSD17B13 and MTARC1 offer protective effects, reducing the risk of severe liver disease despite comorbidities such as obesity, and can mitigate the harmful effects of these risk alleles. Additionally, the potential of polygenic risk scores (PRS) to predict MASLD development and its complications is also discussed, although challenges remain, particularly in underrepresented populations due to the lack of comprehensive catalogues of genetic variation. Understanding these complex gene-gene interactions and the role of the environment underscores the importance of considering epistatic relationships when assessing MASLD risk and developing personalized therapeutic strategies, which could ease the future burden on healthcare systems. · Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly one-third of the global population, with rising incidence due to sedentary lifestyles, obesity, and type 2 diabetes. · It is estimated that nearly 50% of MASLD patients have heritable predisposition genetic variants in genes such as PNPLA3 and TM6SF2, which play significant roles in MASLD development. · Several protective alleles have also been identified, which may mitigate MASLD progression despite genetic variants and environmental risk factors. · Epistatic relationship between predisposing and protective genes can influence Polygenic Risk Score and improve the precision detection and early diagnosis of liver metabolic diseases. · Risk-modifying variants have different allelic frequencies according to the population considered.

Osteoarthritis (OA) is a chronic degenerative joint disease influenced by genetic, environmental, and immunological factors. Vitamin D exerts immunomodulatory and anti-inflammatory effects through the vitamin D receptor (VDR), and genetic variation in the VDR gene may influence susceptibility to OA. However, data from Middle Eastern and Kurdish populations remain limited. This study aimed to evaluate the association between serum vitamin D status and four common VDR gene polymorphisms (FokI, ApaI, TaqI, and BsmI) in Kurdish adults with knee osteoarthritis. A hospital-based case-control study was conducted, including 100 OA patients and 100 healthy controls recruited in Erbil, Iraq. Serum vitamin D levels were measured biochemically, and VDR polymorphisms were genotyped using PCR-RFLP and sequencing. Association analyses were performed for polymorphic loci using univariate logistic regression. No allelic or genotypic variation was detected at the FokI (rs2228570), ApaI (rs7975232), or TaqI (rs731236) loci, indicating allele fixation in this population. In contrast, the BsmI (rs1544410) polymorphism exhibited significant variability. The AA genotype was significantly more frequent among OA patients than controls and was associated with increased odds of OA (OR = 2.26, 95% CI = 1.21-4.23; p = 0.006). The findings indicate that the VDR BsmI polymorphism is associated with knee osteoarthritis in the Kurdish population, whereas FokI, ApaI, and TaqI loci were non-polymorphic. These results highlight population-specific genetic variation within the VDR gene and underscore the need for larger studies incorporating functional validation to clarify the biological relevance of BsmI variation in osteoarthritis.

Weyers acrofacial dysostosis (WAD) is a rare autosomal dominant ciliopathy caused by heterozygous pathogenic variants in the EVC2 gene. The classic phenotype includes short stature, dental anomalies, and nail dysplasia. To date, all reported causative variants are truncating mutations located within the last exon (exon 22). In contrast, pathogenic variants in other regions, particularly splice-site variants, remain poorly characterized. The co-occurrence of WAD and epilepsy has rarely been documented. We performed exome sequencing in a proband with comorbid developmental and epileptic encephalopathy (DEE) and WAD features. A candidate splice-site variant was further investigated using an in vitro minigene splicing assay. Exome sequencing identified a de novo heterozygous splice-site variant in EVC2 (c.451-1G > T). Minigene analysis confirmed that this variant causes complete skipping of exon 4, predicted to lead to an in-frame deletion (p.Tyr151_Leu173del). To our knowledge, this is the first report of a pathogenic splice-site variant in this region of EVC2 associated with WAD and DEE. Our study expands the mutational spectrum of EVC2. It underscores the utility of exome sequencing coupled with functional assays for diagnosing complex cases.

TMEM201, a nuclear membrane protein, is thought to play an important role in tumor progression, but its involvement in lower-grade glioma (LGG) remains unclear. This study aims to investigate the impact of TMEM201 expression on the prognosis, clinical characteristics, and biological behaviors of LGG. RNA expression data from the TCGA, CGGA, and GEO databases were analyzed to explore the correlation between TMEM201 expression and clinical features of LGG. In vitro and in vivo experiments were conducted to assess the effects of TMEM201 knockdown on cell proliferation, migration, and tumorigenic potential. DNA methylation sites associated with TMEM201 were analyzed, and KEGG pathway enrichment was performed to identify the molecular mechanisms underlying TMEM201’s role in LGG. The analysis showed that high TMEM201 expression was associated with poor prognosis, higher WHO grade, and tumor recurrence in LGG patients. Survival analysis confirmed that elevated TMEM201 levels correlated with shorter survival. Knockdown of TMEM201 in SHG44 cells led to significant inhibition of cell proliferation, migration, and tumor formation in vivo. DNA methylation analysis identified key sites regulating TMEM201 expression, and KEGG analysis revealed pathways such as HIF-1, VEGF, and Notch that contribute to tumor progression. TMEM201 acts as a potential oncogene in LGG by influencing key cellular signaling pathways and tumor behaviors. It is an independent risk factor for poor prognosis and may serve as a promising biomarker for diagnosis and personalized treatment. This study provides valuable insights into the molecular mechanisms of LGG progression and highlights TMEM201 as a therapeutic target.

Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in the development and recovery of tracheal injury from septic shock. Nine New Zealand white rabbits were randomized to control (CON), septic shock model (SS), and septic shock norepinephrine treatment (SSNE) groups (each group n = 3). The SS and SSNE groups were injected with lipopolysaccharide to induce septic shock. The SSNE group was administered Ringer lactate with norepinephrine to maintain normal blood pressure. All animals underwent cuffed endotracheal intubation for 2h. The injured tracheal segment was harvested. RNA sequencing was performed to identify the DEGs, followed by bioinformatics analysis, and pathological staining (both HE and Masson) was performed for pathological evaluation. Bioinformatics analysis included principal component analysis (PCA), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network construction. Key findings were validated by qRT-PCR and immunohistochemistry. We obtained 124 upregulated and 28 downregulated DEGs in SS vs. CON groups, along with 60 upregulated and 178 downregulated DEGs in SSNE vs. SS groups. The pathological score showed that trachea tissue in the SS group had the highest score. The protein-protein interaction (PPI) prediction identified APOB and CD36 as the hub genes. The molecular experiments further confirmed that at mRNA and protein levels, APOB was significantly upregulated, while CD36 was significantly downregulated. Subsequent qRT-PCR and immunohistochemical analyses confirmed that APOB expression was significantly upregulated while CD36 was downregulated in the septic shock group, a trend partially reversed by norepinephrine treatment. Our study results suggest that APOB and CD36 may be involved in the pathogenesis of tracheal injury recovery in septic shock patients treated with NE. Not applicable.

BackgroundTranscriptomic analysis is common in large cohort studies but is generally restricted to cells in blood, which limits inferences about organs of interest, and direct organ sampling is mostly infeasible in large cohorts. New techniques for RNA-seq from noninvasive biosamples may provide the opportunity to profile transcriptomes of additional tissues for more organ-relevant insights at scale. We investigated the feasibility and utility of hair follicle gene expression profiling in a multi-center study of chronic obstructive pulmonary disease (COPD).MethodsBulk RNA-seq was performed on hair follicles collected in the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS), a multi-center longitudinal study of COPD (n = 97). The resulting hair follicle gene expression data were characterized and compared both to gene expression in whole blood and bronchial epithelium previously measured in SPIROMICS and to Genotype-Tissue Expression (GTEx) project tissue gene expression by principal component analysis and single-sample gene enrichment analysis, used to estimate hair follicle cell type proportions, and tested for association with disease-relevant lung phenotypes. eQTL discovery was also performed and colocalization with a genome-wide association study for lung function was tested.ResultsHair follicles reliably produced transcriptomic data of sufficient quality and number for cell type composition, which revealed mostly epithelial and fibroblast cells. Comparison to other tissues previously profiled in SPIROMICS and GTEx project demonstrated transcriptomes from hair follicles were much more similar to those from lung parenchyma than blood. Combining these data with rich clinical, imaging, and genomic profiling in SPIROMICS, we found that they provided an attractive approach for discovery of associations with complex lung phenotypes, particularly of the airways. Finally, we investigated hair follicle genetic architecture through expression quantitative trait locus (eQTL) discovery and demonstrated better colocalization with lung-related genetic associations than blood.ConclusionHere, we demonstrated that RNA-seq applied to hair follicle transcriptomic profiling can be scaled up successfully in a multi-center study to yield inferences not available from blood transcriptomics.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12920-025-02270-w.